Can we gain insights into the biology of microglia by studying disease-associated genes?

As the primary defense, immune, and phagocytic cells in the brain, microglia govern multiple aspects of brain development, repair, and aging. In recent years, there has been an increasing appreciation of the contributions of microglia in neurodegenerative, neurodevelopmental, and neuropsychiatric disorders. In particular, the aberrant activation and resolution of microglial responses have been linked to the pathology observed in sporadic or late-onset Alzheimer’s disease. Although genome-wide association studies have revealed a number of genes potentially associated with increased risk of Alzheimer’s disease, and enriched in microglia, large-scale functional analyses of these genes have not been performed to date.

We will exploit the experimental tractability of zebrafish for performing large-scale CRISPR screens to define the functions of genes implicated in brain disorders using live, in vivo imaging. Our expansive functional genomics approach will: a) uncover novel functions of genes associated with neurological diseases; b) reveal important and interesting biology of microglia and macrophages; and c) identify vulnerable signaling pathways that can be targeted for therapeutics.